Interferon Regulatory Factor 5 Regulates the Phagocytosis of Microglia and Alleviate Alzheimer's Pathology

Microglia play a critical role in the pathophysiology of Alzheimer's disease. They are involved in A beta-induced neuroinflammatory responses, regulating the production of inflammatory mediators. Interferon regulatory factor 5 (IRF5) plays a central role in inflammatory diseases in the periphery, the role of which in central nervous system remains elusive. This study aimed to investigate the role of IRF5 in A beta-induced neuroinflammation and the progression of A beta pathology. We found that A beta 1-42 oligomers significantly increased the level of IRF5 in BV2 microglia. The levels of proinflammatory cytokines TNF-alpha, IL-1 beta, and IL-6 were significantly upregulated with A beta treatment. IRF5 knockdown with siRNA in microglia significantly reduced the expression of these proinflammatory factors induced by A beta and promoted A beta phagocytosis. Besides, LC3 upregulation and p62 downregulation were observed in IRF5 knockdown microglia. This was also validated in APP/PS1 mice with IRF5 knockdown, leading to reduced A beta levels in the brain. We conclude that IRF5 mediates A beta-induced microglial inflammatory responses. IRF5 knockdown attenuated A beta-induced inflammatory responses and promoted the phagocytosis and autophagy of A beta by microglia.